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Microgel particles for the delivery of bioactive materials

a bioactive material and microgel technology, applied in the direction of microcapsules, powder delivery, peptides, etc., can solve the problems of protein-based vaccines, ineffective vaccine generation strategies based on live attenuated viruses, and limited clinical success of protein-based vaccines

Inactive Publication Date: 2006-06-06
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0019]The above compositions preferably contain a bioactive material which is selected from the group consisting of consisting of polysaccharides, proteins, DNA and RNA. The DNA may be unmethylated (e.g. bacterial plasmid) DNA, which evokes an immune response in mammals. The biological material may also be a protein or other chemical antigen that is delivered to the lysosome of an immune cell for antigen presentation. This provides an effective vaccine.

Problems solved by technology

Traditional vaccination strategies, based on live attenuated viruses, have been ineffective at generating vaccines against these diseases, largely as result of their high toxicity.
However, the clinical success of protein-based vaccines has been limited, due to delivery problems, and new protein delivery vehicles are needed that can enhance the efficacy of protein-based vaccines.
A key limitation of current protein-based vaccines is their inability to activate cytotoxic T lymphocytes (CTL).
However, PLGA based delivery vehicles have been problematic because of their poor water solubility.
A key problem in the field of hydrogel research is the development of materials that can release their contents in response to pathological stimuli, allowing for the targeting of protein therapeutics to diseased tissues and cells.
At present, micron sized hydrogels have been synthesized using crosslinkers that do not degrade under biological conditions, and hence have had limited success in drug delivery applications.

Method used

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  • Microgel particles for the delivery of bioactive materials
  • Microgel particles for the delivery of bioactive materials
  • Microgel particles for the delivery of bioactive materials

Examples

Experimental program
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Effect test

example 1

Synthesis and Delivery of Microgels

[0137]Referring now to FIG. 3, an exemplary process for the synthesis of a microgel particle for pH-dependent degradation is shown. A polymerizable acrylic group 100 is added to the bisacrylamide methoxybenzaldehyde acetal crosslinker 110 (which is described in the following example) wherein R1=(a) of FIG. 2 and R2=aryl-methoxy. The polymerization reaction is carried out by inverse microemulsion, initiated by an initiator such as TMEDA and diammonium persulfate and carried out in the presence of bioactive particle 40, and carried out in the presence of bioactive particle 40.

[0138]At neutral pHs, the bisacrylamide methoxybenzaldehyde acetal crosslinker 110 remains intact and the release of entrapped bioactive material 40 is significantly slower or not at all. Under acidic conditions, the acetal group hydrolyses and increases the pore size of microgels made with it, releasing the entrapped bioactive materials 40, and degraded particles, in the form o...

example 2

Synthesis of a Bisacrylamide Methoxy Benzaldehyde Acetal Crosslinker

[0139]Referring to FIG. 4, the bisacrylamide methoxy benzaldehyde acetal crosslinker 110 was synthesized in two steps. The first step was acetal formation with hydroxy-trifluoroacetamide and methoxy benzaldehyde using the procedure of Roelofsen et al., Recueil, 90, 1141–1152 (1971, which gave a 70% yield of bistrifluoroacetamide methoxy benzaldehyde acetal 410 after chromatography. In the second step, the intermediate was then deprotected with 6N NaOH and reacted with acryloyl chloride to yield the crosslinker 110 (FIG. 3) in 40% yield after chromatography. In the crosslinker 110, R2 (according to the generic formula of FIG. 2) was methoxy benzaldehyde (methoxy aryl).

example 3

Synthesis of an Autocatalytic Bisacryloyl Acetal Crosslinker

[0140]A strategy for synthesis of an autocatalytic bisacryloyl acetal crosslinker involves the condensation of one molecule of carbonyl compound such as a benzaldehyde with two molecules of a carboxylic acid or derivative thereof. In this case, R1=(c) of FIG. 2, and R2=aryl-H.

[0141]FIG. 5A shows a bisacrylic benzaldehyde acetal crosslinker 530 obtained by incorporation of two acrylic acid moieties in an acetal like structure with benzaldehyde. Referring now to FIG. 5A, para methoxy benzaldehyde 510 is reacted with acrylic anhydride 520 in the presence of sulfuric acid to form the autocatalytic bisacrylic benzaldehyde acetal crosslinker 530. Also shown is an alternative synthesis is to react dibromo-toluene with sodium acrylate 550 to form the crosslinker 530.

[0142]In addition to the same acid degradable linkage, hydrolysis of the autocatalytic crosslinker under mild acidic conditions proceeds with release of two molecules o...

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Abstract

Novel microgels, microparticles and related polymeric materials capable of delivering bioactive materials to cells for use as vaccines or therapeutic agents. The materials are made using a crosslinker molecule that contains a linkage cleavable under mild acidic conditions. The crosslinker molecule is exemplified by a bisacryloyl acetal crosslinker. The new materials have the common characteristic of being able to degrade by acid hydrolysis under conditions commonly found within the endosomal or lysosomal compartments of cells thereby releasing their payload within the cell. The materials can also be used for the delivery of therapeutics to the acidic regions of tumors and sites of inflammation.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Patent Application No. 60 / 368,576, which was filed on Mar. 29, 2002, which is incorporated by reference in its entirety.STATEMENT OF GOVERNMENT SUPPORT[0002]This invention was made during work partially supported by the U.S. Department of Energy under Contract No. DE-AC03-76SF00098. The government has certain rights in this invention.BACKGROUND OF THE INVENTION[0003]1. Field of the Invention[0004]This invention generally relates to the field of cross-linked hydrogel polymers formed into microgels for use in delivery of bioactive materials such as antigens, DNA and other therapeutics.[0005]2. Description of the Related Art[0006]There is a great need for the development of vaccines against AIDS, Hepatitis C, cancer and other diseases. Traditional vaccination strategies, based on live attenuated viruses, have been ineffective at generating vaccines against these diseases, largely as result...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K48/00A61K31/715A61K39/00A61K9/14A61K31/00A61K9/00A61K9/16A61K9/51A61K31/70A61K39/39C08B37/02
CPCA61K9/1635A61K9/1652A61K9/5161A61K9/5192C08B37/0021A61K39/39B82Y5/00A61K31/70A61K2039/53A61K2039/55555
Inventor FRECHET, JEAN M. J.MURTHY, NIREN
Owner RGT UNIV OF CALIFORNIA
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